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Mechanisms of cell death in polyglutamine expansion diseases

Marta M Lipinski1, Junying Yuan

  • 1Harvard Medical School, Department of Cell Biology, 240 Longwood Ave, Boston MA 02115, USA.

Current Opinion in Pharmacology
|March 17, 2004
PubMed

Insights

Abnormal protein aggregation in neurodegenerative diseases is complex. Targeting the upstream formation and degradation of mutant protein aggregates may offer effective neuroprotective therapies.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Abnormal protein aggregation is a key feature of neurodegenerative diseases.
  • Mechanisms of protein aggregate-induced neurodegeneration are not fully understood.
  • Polyglutamine expansion diseases involve various cellular dysfunctions.

Purpose of the Study:

  • To explore mechanisms of neurodegeneration in polyglutamine expansion diseases.
  • To propose therapeutic strategies targeting upstream mechanisms of neurotoxicity.

Main Methods:

  • The study reviews proposed mechanisms of neuronal death.
  • It discusses the impact of expanded polyglutamine expression on neuronal function.

Main Results:

  • Multiple pathways, including caspase activation, transcriptional interference, and axonal transport obstruction, are implicated in polyglutamine disease neurodegeneration.
  • Expanded polyglutamine expression adversely affects neuronal survival and function.

Conclusions:

  • Effective therapies may require targeting upstream mechanisms.
  • Inhibiting intraneuronal aggregate formation and enhancing mutant protein degradation are proposed therapeutic strategies.

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